L-Canavanine L-2-amino-4-(guanidinooxy)butyric acid!, a nonprotein amino acid found in certain leguminous plants.sup.37, is a structural analog of L-arginine in which the terminal methylene group is replaced by oxygen. L-Canavanine, a substrate for arginyl-tRNA-synthetase, is incorporated into newly synthesized protein in place of arginine to create structurally aberrant and dysfunctional proteins.sup.38. Available evidence supports the contention that an important biochemical basis for canavanine's insecticidal and antitumor activities is the formation of dysfunctional canavanine-containing proteins..sup.39,40
More than 26,000 people die each year in our country from pancreatic adenocarcinoma.sup.1. Death is the inevitable consequence to more than 90% of patients with this disease. It is the fourth most common cause of cancer death in men and the fifth most common for women.sup.2. Overall, it is the fourth most common carcinoma after those of the lung, colon and breast.sup.3. The incidence of this disease is linear with age to sixty but its occurrence increases markedly in the seventh or eighth decade of life.sup.4. There are several different histologies associated with cancer of the pancreas including small cell cancer, cystadenocarcinoma, islet cell tumors, lymphoma and carcinoid; however, 75-80% of the cases involve adenocarcinomas of ductal origin.sup.5. The only definitive risk factor in pancreatic cancer is cigarette smoking. A typical smoker accepts up to four times the risk of a nonsmoker.sup.6.
Located in the upper abdomen in the retroperitoneum, the pancreas is associated intimately with many major structures including the portal vein, stomach, duodenum, common bile duct and the superior mesenteric artery. As the tumor grows, the patient's symptoms result from tumor infiltration of surrounding structure causing pain, nausea, vomiting, weight loss and jaundice. The latter condition presents symptoms in no more than one half of the patients. Once tumor infiltration occurs other structures such as the portal vein become affected and this precludes curative resectioning of the pancreas.
Effective treatment of pancreas cancer must achieve two difficult goals: control of the primary tumor mass, both initially and subsequently, and treatment of the metastatic tumor cells. As a result of its insidious onset, the diagnosis of pancreas cancer is delayed frequently for several months. This delay has profound implications, since metastatic spread to the liver or lymph nodes has been observed at a time of diagnosis in 60% of patients, and this factor diminishes the prospect for long-term survival.sup.7. Also, there are no known specific markers of carcinoma of the pancreas and it is asymptomatic in its early stage.sup.8.
Conventional Therapy for Pancreatic Cancer
Currently, surgery is the primary and only curative therapy for pancreas cancer. However, only 15-25% of tumors are resectable at the time of diagnosis.sup.9 and regrettably only 10-20% of patients resected will survive more than two years.sup.10. With these less than satisfactory surgical results, present day therapy has evolved in two directions: palliation of symptoms and aggressive multimodality treatment regimes which combine surgery with chemotherapy and radiation treatment.
Palliative therapy has become a major thrust of current treatment. Initial relief of symptoms has relied on surgery with surgical bypass of gastric outlet obstruction.sup.11 and operative bypass of biliary obstruction.sup.12. Subsequent symptomatic treatment has centered around endoscopic placement of biliary stents to bypass tumors blocking the biliary tract.sup.13 and/or percutaneous placement of bypass conduits.sup.14.
Aggressive multimodality therapy combining chemotherapy and radiation therapy with surgery has been the response of choice when surgery alone was not effective. Radiation has been the cornerstone of therapy for unresectable cancer of the pancreas and 5-fluorouracil (5-FU) chemotherapy has been an important adduct to radiation treatment in these patients.sup.15. However, despite these valiant efforts, no patient survives five years.
A single, small randomized trial showed significant benefit from combined radiation and chemotherapy given two years after operation.sup.16. While this study was limited by an inadequate number of patients, nonetheless there was benefit to patients receiving multi-modality treatment.
Effective radiotherapy needs to maximize exposure of the affected tissues while sparing normal surrounding tissues. Interstitial therapy, where needles containing a radioactive source are embedded in the tumor, has become a valuable new approach. In this way, large doses of radiation can be delivered locally while sparing the surrounding normal structures.sup.17. Intraoperative radiotherapy, where the beam is placed directly onto the tumor during surgery while normal structures are moved safely away from the beam, is another specialized radiation technique. Again, this achieves effective irradiation of the tumor while limiting exposure to surrounding structures. Despite the obvious advantage of approaches predicated upon local control of the irradiation, patient survival is not significantly improved.sup.18,19.
The foundation of chemotherapy for carcinoma of the pancreas has employed 5-FU.sup.20. Here too, the prognosis is bleak; no better than 10-15% of patients treated with 5-FU will experience a significant reduction in tumor size; overall survival rates are not improved. The addition of other chemotherapeutic agents such as cis-platin or adriamycin has not dramatically improved disease management.sup.20). For this reason, attempts to augment the intrinsic activity of 5-FU have been undertaken. On one approach, 5-FU is converted to 4-fluorodeoxyuridine monophosphate (FdUMP) which binds covalently to thymidylate synthase (EC 2.1.1.45). This competitive inhibitor disrupts DNA replication by curtailing deoxyuridine monophosphate anabolism to deoxythymidine.
Reduced folates such as leucovorin are a necessary cofactor for FdUMP binding to thymidylate synthase.sup.21. Cancer cells depauperate in reduced folate are resistant to 5-FU chemotherapy, but that resistance can be circumvented by providing exogenous reduced folate.sup.22. While 5-FU plus leucovorin relative to 5-FU alone has proven efficacious in treating colon cancer, patients with pancreas cancer received no benefit by receiving these two drugs in combination.sup.23.
5-Fluorouracil can also be converted to 5-fluorouridine monophosphate which can be incorporated into mRNA thereby affecting protein translation. N-N- (phosphonacetyl) -L-aspartic acid (PALA) inhibits the transformation of aspartic acid to orotidine monophosphate which is converted subsequently to uridine monophosphate. The use of PALA provides a means of depleting essential uridine monophosphate. In the absence of uridine monophosphate, fluorouridine monophosphate is incorporated preferentially into mRNA which promotes cell death. Preliminary data from experiments employing high dose (2,600 mg/m.sup.2) 5-FU after pretreatment with PALA have been promising, as significant tumor reduction has been noted in 5 of 6 patients.sup.24. However, subsequent phase II data have been less positive.sup.25 with only one patient in 29 achieving any benefit. While new experimental efforts in treating pancreas cancer have been initiated, their limited success emphasizes the need for radically new approaches in the management of this devastating disease. The present invention provides an additional alternative for the treatment of cancers, particularly pancreatic cancer, by providing for a pharmaceutical composition comprising canavanine, and a method of treatment of cancer, particularly pancreatic cancer with canavanine.